The Ras proteins are a family of guanine nucleotide binding GTPases that play a pivotal role in mediating cell growth, differentiation and development. (Barbacid, Annual Review of Biochemistry, Vol. 56, p. 779 (1987)). In mammalian cells, there are three ras genes that encode four Ras proteins, H, N, KA and KB-Ras. (E. C. Lerner et al., Anti-Cancer Drug Design, Vol. 12, pp. 229-238 (1997)). Mutations in Ha-ras, Ki-ras and N-ras, and the over-expression of Ras has been observed in approximately 30% of all human cancer tissues. (Lerner et al., S. L. Graham, Exp. Opin. Ther. Patents, Vol. 5, no. 12, pp. 1269-1285 (1995); T. Hiwasa, Oncology Reports, Vol. 3, pp. 7-14 (1996); S. L. Graham and T. M. Williams, Exp. Opin. Ther. Patents, Vol. 6, no. 12, pp. 1295-1304 (1996)). Although several steps are involved in modifying Ras proteins, farnesylation is the only step which is required and sufficient for Ras transforming activity. (E. C. Lerner et al.) Therefore, farnesyl-transferase (FTase) serves as an attractive target for the development of a potential new class of anti-cancer agents. (E. C. Lerner et al.) It has been noted that routes to inhibitors of Ras farnesylation are apparent from an examination of the substrate specificities of the enzyme. One can design analogs either of the lipid, or of the peptide sequence to which the lipid is transferred. Such compounds must be stable, and readily cross the cell membrane to gain access to the cytosolic transferase. (J. E. Buss and J. C. Marsters, Jr., Chemistry and Biology, Vol. 2, pp. 787-791 (1995)).
Compounds that incorporate 1,5 disubstituted imidazole moieties have been observed to be farnesyltransferase inhibitors. (WO 96/30343 published on Oct. 30, 1996). It is therefore desirable to discover a process for making 1,5 disubstituted imidazoles that is efficient, inexpensive, safe and operationally facile. Prior methods for synthesizing 1,5 disubstituted imidazoles involved using starting materials such as 5-hydroxymethylimidazole hydrochloride, which is expensive and not readily available in bulk. Such processes also utilized high molecular weight triphenylmethyl (trityl) protecting groups but these limit the efficiency of the process. The synthesis of 1,5 disubstituted imidazoles from primary amines, dihydroxyacetone and potassium thiocyanate via thioimidazoles has been reported in the classical synthetic chemical literature. (Marckwald, Chem Ber. 1892, 25, 2354) A more recent published example of this is by J. M. Duncia et al., J. Med. Chem. 1990, 33, 1312-1330. Literature protocols for the dethionation of 2-mercaptoimidazoles involved treatment with nitric acid. Such a procedure was found to result in the sudden and violent release of nitrogen oxide gases and gave variable results. The amine derivative could also be prepared using an azide displacement and reduction. However, the use of azides for such syntheses presents safety issues as well.
It is therefore an object of this invention to provide a process for the synthesis of 1,5 disubstituted imidazoles that employs commodity chemicals which are readily available and inexpensive.
It is a further object of this invention to provide a process for the synthesis of 1,5 disubstituted imidazoles that is more efficient by eliminating the use of high molecular weight trityl protecting groups.
It is a further object of this invention to provide a process for the synthesis of 1,5 disubstituted imidazoles that is safer by eliminating the use of azides and nitric acid.